Summary of work: Sonodynamic therapy is a promising new modality for cancer treatment based on the synergistic effects of cell killing by a combination of sonosensitizer and ultrasound. Ultrasound can penetrate deeply into tissue and can be focused in a small region of tumor to activate non-toxic molecules (e.g. porphyrins ) thus minimizing undesirable side effects. The experimental evidence suggests that sonosensitization is due to the chemical activation of sonosensitizers inside or in close vicinity of hot collapsing cavitation bubbles to form sensitizer-derived radicals either by direct pyrolysis of the sensitizer at the water-gas interface or due to the reactions of hydrogen atoms and hydroxyl radicals formed by the pyrolysis of water. The free radicals derived from the sonosensitizer (mostly carbon-centered) react with oxygen to form peroxyl and alkoxyl radicals. Unlike OH radicals and H atoms which are formed by pyrolysis inside cavitation bubbles, the reactivity of alkoxyl and peroxyl radicals with organic compounds in biological media is much lower and hence they have a higher probability of reaching critical cellular sites. Our recent studies have shown that the long chain ( C5-C8 ) n-alkyl glucopyranosides completely inhibit ultrasound induced cytolysis (3). This protective effect has possible applications in HIFU ( High intensity focused ultrasound ) for tumor treatment and in ultrasound assisted drug delivery and gene therapy. n-Alkyl glucopyranosides with hexyl ( 5mM ), heptyl ( 3mM ), octyl ( 2mM ) n-alkyl chains protected 100 % of HL-60 cells in vitro from 1.057 MHz ultrasound induced cytolysis under a range of conditions which resulted in 35% to 100% cytolysis in the absence of glucopyranosides. However the hydrophilic methyl-beta-D-glucopyranoside did not protect cells. The surface active n-alkyl glucopyranosides accumulate at the gas-liquid interface of cavitation bubbles. The OH radicals and H atoms formed in collapsing cavitation bubbles react by H-atom abstraction from either the n-alkyl chain or the glucose moiety of the n-alkylglucopyranosides. Owing to the high concentration of the long chain surfactants at the gas-liquid interface of cavitation bubbles , the initially formed carbon radicals on the alkyl chains are transferred to the glucose moieties to yield radicals which react with oxygen leading to the formation of hydrogen peroxide. Our recent measurements (2) of the hydrogen peroxide yields at 614 kHz and 1.057 MHz from oxygen-saturated solutions of long chain ( hexyl , octyl ) glucopyranosides compared with methyl-beta-D-glucopyranoside are consistent with the proposed mechanism of sonoprotection. This sequence of events prevents sonodynamic cell killing by initiation of lipid peroxidation chain reactions in cellular membranes by peroxyl and/or alkoxyl radicals. The effect of ultrasound frequency (from 47 kHz to 1 MHz ) on the ability of a homologous series of n-alkylglucopyranosides to protect cells from ultrasound-induced cytolysis was investigated. Comparisons of the protective ability of this series of n-alkylglucopyranosides with our earlier studies of their accumulation at the gas/solution interface of cavitation bubbles show that the ability of these surfactants to accumulate at this gas/solution interface is governed by the dynamic absorption properties and not the equilibrium absorption properties of these surfactants. Therapeutic applications of ultrasound to drug activation, apoptosis induction, gene transfer and changes of gene expression were reviewed (1). 5-Aminolevulinic acid ( a precursor for the biosynthesis of protoporphyrin IX which is used in photodynamic therapy ) combined with intracellular citrate capped gold nanoparticles of specific sizes ( e.g. 5nm ) was found to be effective in killing cultured cells ( HL-60, HL-525 and MCF-7 ) even in the absence of light. 1. Yoshida,T., Kondo, T., Ogawa, R., Zhao, Q., Hassan, M., Watanabe, A., Takasaki, I., Tabuchi, Y., Shoji, M., Kudo, N., Feril, L., Tachibana, K., Buldakov, M., Honda, T., Tsukada, K.& Riesz, P., Molecular therapy by ultrasound. The mechanism of drug activation, apoptosis induction, gene transfer, and change of gene expressions. Thermal Medicine ( Japan), (2007) in press 2. Cheng, J.Y. & Riesz, P., Mechanism of the protective effects of long chain n-alkyl glucopyranosides against ultrasound-induced cytolysis of HL-60 cells. Ultrasonics Sonochemistry 14, 667-671 (2007) 3. Sostaric, J.Z., Miyoshi, N., Riesz, P., De Graff, W.G. & Mitchell, J.B., n-Alkyl glucopyranosides completely inhibit ultrasound-induced cytolysis. Free Radical Biology & Medicine 39, 1539-1548, (2005) 4.. Feril, L.B., Tsuda, Y., Kondo, T., Zhao, Q.L., Ogawa, R., Cui, Z.G., Tsukada, K. & Riesz P., Ultrasound-induced killing of monocytic U937 cells enhanced by 2,2'-azobis(2-amidinopropane) dihydrochloride. Cancer Science 95, 181-185 (2004). 5.. Feril, L., Kondo, T., Takaya, K. & Riesz, P., Enhanced ultrasound-induced apoptosis and cell lysis by a hypotonic medium. International Journal of Radiation Biology 80, 165-175 (2004). 6.. Rosenthal, I., Sostaric, J. & Riesz, P., Sonodynamic therapy - a review of the synergistic effects of drugs and ultrasound. Ultrasonics Sonochemistry 11, 349-363 (2004). 7.. Rosenthal, I., Sostaric, J. & Riesz, P., Enlightened sonochemistry. Research on Chemical Intermediates 30, 685-701 (2004)